研究者詳細 - 豊國　伸哉

論文 - 豊國　伸哉

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DNA base modifications in renal chromatin of wistar rats treated with a renal carcinogen, ferric nitrilotriacetate

Toyokuni S., Mori T., Dizdaroglu M.

International Journal of Cancer 57 巻 ( 1 ) 頁： 123 - 128 1994年4月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Cancer

Ferric nitrilotriacetate (Fe‐NTA) causes renal proximal tubular necrosis, a consequence of iron ion‐mediated free‐radical‐associated damage, that finally leads to a high incidence of renal ad en oca re in dm a in male rats and mice. We have investigated the levels of typical hydroxyl radical‐induced DNA base modifications in renal chromatin of male Wistar rats treated with a single or repeated administrations of Fe‐NTA. Five pyrimidine‐derived and 5 purine‐derived modified DNA bases were identified and quantified by gas chromatography/mass spectrometry with selected‐ion monitoring. The modified bases were 5‐hydroxy‐5‐methylhydantoin, 5‐(hydroxymethyl)uracil, 5‐hydroxy‐cytosine, thymine glycol, 5,6‐dihydroxyuraril, 4,6‐diamino‐5‐form‐amidopyrimidine, 8‐hydroxyadenine, xanthine, 2‐hydroxyadenine and 8‐hydroxyguanine. The amounts of most of these compounds were significantly increased over control levels in renal chromatin of Fe‐NTA‐treated rats as measured 3 and 24 hr after treatment. Elevated levels of modified bases were accompanied by proximal tubular necrosis. On the 19th day, however, accumulation of modified DNA bases was not observed. Morphologically, scattered karyomegaiic cells were seen in the proximal tubules, but necrosis was rarely found. Some of the identified DNA base lesions are known to be promutagenic., although others have not been investigated. Presence of modified DNA bases concomitant with necrosis and regeneration of the renal proximal tubules may be a critical step in Fe‐NTA‐induced carcinogenesis. © Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

DOI： 10.1002/ijc.2910570122

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FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE 査読有り国際誌

TOYOKUNI S, UCHIDA K, OKAMOTO K, HATTORINAKAKUKI Y, HIAI H, STADTMAN ER

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 91 巻 ( 7 ) 頁： 2616 - 2620 1994年3月

Formation of 4-hydroxy-2-nonenal-modified proteins in the renal proximal tubules of rats treated with a renal carcinogen, ferric nitrilotriacetate

Toyokuni S., Uchida K., Okamoto K., Hattori-Nakakuki Y., Hiai H., Stadtman E.

Proceedings of the National Academy of Sciences of the United States of America 91 巻 ( 7 ) 頁： 2616 - 2620 1994年3月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America

An iron chelate, ferric nitrilotriacetate (Fe-NTA), induces proximal tubular necrosis, a consequence of lipid peroxidation, that finally leads to a high incidence of renal adenocarcinoma in rodents. Lipid peroxidation as monitored by formation of thiobarbituric acid-reactive substances and free 4- hydroxy-2-nonenal (HNE) was observed in the kidney homogenates of rats treated with Fe-NTA. Based on the fact that HNE is capable of reacting with cellular proteins, we attempted to detect the localization of HNE-modified proteins in rat kidney tissues with an immunohistochemical procedure. By means of an immunohistochemical technique using polyclonal antibody against the HNE-modified proteins, it was shown that HNE-modified proteins are formed in the target cells of this carcinogenesis model. HNE-modified proteins were detected in the renal proximal tubules 1 hr after i.p. administration of Fe- NTA (15 mg of iron per kg). Intense positivity was found in the cells with degeneration. After 6 hr, the level of HNE-protein conjugates decreased due to the subsequent necrosis. The intensity of the immunochemical reaction with HNE-modified proteins increased in parallel with an increase in the amounts of thiobartituric acid-reactive substances and free HNE that were found. Furthermore, histochemical detection of aldehydes by cold Schiff's reagent demonstrated that location of aldehydes was identical to that of the HNE- modified proteins determined by immunohistochemical procedures. It would thus appear that the production of HNE, a genotoxic and mutagenic aldehyde, and its reaction with proteins may play a role in Fe-NTA-induced renal carcinogenesis.

DOI： 10.1073/pnas.91.7.2616

Scopus

FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE 査読有り国際誌

TOYOKUNI S, UCHIDA K, OKAMOTO K, HATTORINAKAKUKI Y, HIAI H, STADTMAN ER

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 91 巻 ( 7 ) 頁： 2616 - 2620 1994年3月

ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL KH MICE

OKAMOTO K, YAMADA Y, OGAWA MS, TOYOKUNI S, NAKAKUKI Y, IKEDA H, YOSHIDA O, HIAI H

CANCER RESEARCH 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL KH STRAIN MICE

YAMADA Y, MATSUSHIRO H, OGAWA MS, OKAMOTO K, NAKAKUKI Y, TOYOKUNI S, FUKUMOTO M, HIAI H

CANCER RESEARCH 54 巻 ( 2 ) 頁： 403 - 407 1994年1月

ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL KH MICE

OKAMOTO K, YAMADA Y, OGAWA MS, TOYOKUNI S, NAKAKUKI Y, IKEDA H, YOSHIDA O, HIAI H

CANCER RESEARCH 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

Genetic predisposition to pre-B lymphomas in SL/Kh strain mice.

Yamada Y, Matsushiro H, Ogawa MS, Okamoto K, Nakakuki Y, Toyokuni S, Fukumoto M, Hiai H

Cancer research 54 巻 ( 2 ) 頁： 403 - 7 1994年1月

Abnormal bone marrow B-cell differentiation in pre-B lymphoma-prone SL/Kh mice.

Okamoto K, Yamada Y, Ogawa MS, Toyokuni S, Nakakuki Y, Ikeda H, Yoshida O, Hiai H

Cancer research 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

Genetic Predisposition to Pre-B Lymphomas in SL/Kh Strain Mice 査読有り国際誌

Yamada Y., Matsushiro H., Ogawa M.S., Okamoto K., Nakakuki Y., Toyokuni S., Fukumoto M., Hiai H.

Cancer Research 54 巻 ( 2 ) 頁： 403 - 407 1994年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Research

Genetic predisposition of SL/Kh mice to spontaneous pre-B lymphomas was investigated in crosses between SL/Kh and NFS/N, another inbred strain of mice lacking endogenous ecotropic provirus and spontaneous lymphoma. (SL/Kh x NFS/N) F! hybrids developed lymphomas similar to those in SL/Kh but at a lower frequency and with a longer latent period. Of 83 backcross mice to NFS/N, 22 developed hemopoietic tumors: 8 were diffuse lymphoblastic lymphomas; 2 were myeloid leukemias arising by 12 months of age; and 12 were follicular center cell lymphomas found later in life. Of 6 endogenous ecotropic proviruses in SL/Kh, 2 were expressed in (SL/Kh x NFS) Fx backcrossed to NFS. One, encoded by a 27-kilobase EcoSl fragment, was closely linked to Gpi-1” on chromosome 7 and its expression seemed to be a prerequisite for the occurrence of all types of hemopoietic tumors. Microsatellite analysis of the backcross generation revealed multiple host genetic factors determining susceptibility to tumors. An allele derived from SL/Kh, mapped in the major histocompatibility locus on chromosome 17, was essential for development of early onset tumors. This locus was designated as Esl-1 (early lymphoma of SL-1). On the other hand, follicular center cell lymphomas developed mostly in the backcross mice homozygous for the NFS/N derived allele at the D4MIT17-linked locus, designated as foc-1 (follicular center cell lymphoma-1), on chromosome 4. © 1994, American Association for Cancer Research. All rights reserved.

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Genetic Predisposition to Pre-B Lymphomas in SL/Kh Strain Mice 国際誌

Yamada Y, Matsushiro H, Ogawa M.S, Okamoto K, Nakakuki Y, Toyokuni S, Fukumoto M, Hiai H

Cancer Research 54 巻 ( 2 ) 頁： 403 - 407 1994年1月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Research

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Abnormal Bone Marrow B-Cell Differentiation in Pre-B Lymphoma-prone SL/Kh Mice 査読有り国際誌

Okamoto K., Yamada Y., Ogawa M.S., Toyokuni S., Nakakuki Y., Ikeda H.

Cancer Research 54 巻 ( 2 ) 頁： 399 - 402 1994年1月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Cancer Research

SL/Kh mice spontaneously develop pre-B lymphomas with surface phenotypes of B220+, BP-1+, Thy-1-, and surface immunoglobulin negative. The immunoglobulin heavy chain of lymphoma is clonally rearranged but the light chain gene remains in germline configuration. Studying prelymphoma stage SL/Kh bone marrow (BM), we found unusual multiclonal expansion of BP-1+ pre-B cells [34.8 + 5.8% (mean - SD)] by 4 weeks of age, whereas there were far fewer of such cells in most other laboratory strains (8 - 5%). The BP-1+ cells did not express surface immunoglobulin, Thy-1.1, or c-kit. Therefore, they seemed to belong to the pre-B II category. Increased numbers of BP-1+ cells were seen in Fx hybrids between SL/Kh and NFS/N; thus it was apparently a dominant heritable property of SL/Kh mice. Emergence of this population was independent of expression of endogenous ecotropic virus, since they were present in BMs of the Yt hybrid to C4W (Fv-4r) and were not inhibited by neonatal injection of maternal resistance factor. In the radiation chimeras SL/Kh - BALB/c, BP-1+ cells appeared abundantly (29.0 - 3.8%), whereas in the reciprocal chimeras BALB/c - SL/Kh, for fewer (5.5 - 2.3%) appeared. Therefore, expansion of BP-1+ cells in prelymphomatous BM is a property of SL/Kh stem cells rather than BM microenvironments. © 1994, American Association for Cancer Research. All rights reserved.

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ALTERATION OF THE DEOXYGUANINE NUCLEOTIDES TO 8-HYDROXYDEOXYGUANOSINE IN HUMAN RENAL-CELL CARCINOMA

OKAMOTO, K; YOSHIDA, O; HATTORINAKAKUKI, Y; HIAI, H; TOYOKUNI, S

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 447 - 448 1994年

FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE

TOYOKUNI, S; UCHIDA, K; OKAMOTO, K; HATTORINAKAKUKI, Y; HIAI, H; STADTMAN, ER

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 171 - 172 1994年

FORMATION OF 4-HYDROXY-2-NONENAL-MODIFIED PROTEINS IN THE RENAL PROXIMAL TUBULES OF RATS TREATED WITH A RENAL CARCINOGEN, FERRIC NITRILOTRIACETATE 国際誌

TOYOKUNI, S, UCHIDA, K, OKAMOTO, K, HATTORINAKAKUKI, Y, HIAI, H, STADTMAN, ER

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 171 - 172 1994年

ALTERATION OF THE DEOXYGUANINE NUCLEOTIDES TO 8-HYDROXYDEOXYGUANOSINE IN HUMAN RENAL-CELL CARCINOMA 査読有り国際誌

OKAMOTO, K, YOSHIDA, O, HATTORINAKAKUKI, Y, HIAI, H, TOYOKUNI, S

FRONTIERS OF REACTIVE OXYGEN SPECIES IN BIOLOGY AND MEDICINE 1058 巻頁： 447 - 448 1994年

ABNORMAL BONE-MARROW B-CELL DIFFERENTIATION IN PRE-B LYMPHOMA-PRONE SL/KH MICE

OKAMOTO, K; YAMADA, Y; SHIMADA, M; TOYOKUNI, S; NAKAKUKI, Y; HIAI, H

EXPERIMENTAL HEMATOLOGY 21 巻 ( 8 ) 頁： 1126 - 1126 1993年8月

GENETIC PREDISPOSITION TO PRE-B LYMPHOMAS IN SL/KH STRAIN MICE

YAMADA, Y; SHIMADA, M; OKAMOTO, K; TOYOKUNI, S; NAKAKUKI, Y; FUKUMOTO, M; HIAI, H

EXPERIMENTAL HEMATOLOGY 21 巻 ( 8 ) 頁： 1118 - 1118 1993年8月

INDUCTION OF OXIDATIVE SINGLE-STRAND AND DOUBLE-STRAND BREAKS IN DNA BY FERRIC CITRATE

TOYOKUNI S, SAGRIPANTI JL

FREE RADICAL BIOLOGY AND MEDICINE 15 巻 ( 2 ) 頁： 117 - 123 1993年8月

INDUCTION OF OXIDATIVE SINGLE-STRAND AND DOUBLE-STRAND BREAKS IN DNA BY FERRIC CITRATE 査読有り

S TOYOKUNI, JL SAGRIPANTI

FREE RADICAL BIOLOGY AND MEDICINE 15 巻 ( 2 ) 頁： 117 - 123 1993年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：PERGAMON-ELSEVIER SCIENCE LTD

The relative risk of primary hepatocellular carcinoma in genetic hemochromatosis (GH) is estimated at over 200 times as that of control populations. Recently, ferric ion chelated to citrate (Fe-citrate) was identified as the major non-transferrin-bound iron in the serum of GH patients. We investigated whether low concentration of Fe-citrate plus reductant could damage supercoiled plasmid DNA under physiological pH and ionic strength. Incubation of Fe-citrate with either H2O2, L-ascorbate, or L-cysteine induced single- and double-strand breaks in supercoiled plasmid pZ189 in a concentration- and time-dependent fashion. DNA strand breaks produced by Fe-citrate plus H2O2 increased at reduced pH (less-than-or-equal-to 6.9). Catalase and free radical scavengers inhibited the DNA breakage produced by Fe-citrate in combination with each reductant, suggesting that H2O2 and finally .OH are responsible DNA damaging species. The catalytic ability of Fe-citrate to induce DNA strand breaks, particularly double-strand breaks (DSBs), may contribute to the carcinogenic processes observed in GH.

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